Abstract Systemic lupus erythematosus (SLE) and autoimmune thyroid disease are frequently coexisting autoimmune conditions that reflect shared mechanisms of immune dysregulation and polyautoimmunity. This narrative review examines the overlap in pathophysiology, epidemiology, diagnostic considerations, and clinical management of these disorders. Evidence indicates that patients with SLE have a higher prevalence of thyroid dysfunction and antithyroid antibodies compared with the general population, with hypothyroidism—particularly subclinical hypothyroidism—being more common than hyperthyroidism. Shared pathogenic features include genetic susceptibility, B‐cell hyperactivity, autoantibody production, and T‐helper cell–mediated immune responses. Clinically, overlapping nonspecific symptoms and the presence of euthyroid sick syndrome complicate diagnosis, necessitating routine thyroid function and antibody screening in SLE patients. Management of thyroid dysfunction in SLE generally follows standard endocrine guidelines; however, immunosuppressive therapies used in SLE may influence thyroid function and autoimmunity. Recognition of this overlap is essential for optimizing patient outcomes through early detection and integrated care. Further research is needed to clarify causal mechanisms and to develop targeted therapeutic strategies addressing shared immune pathways.
Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, structural damage, and disability. Methotrexate (MTX) is the first‐line treatment; however, up to one‐third of patients exhibit an inadequate response. This systematic review aimed to identify clinical, serological, genetic, pharmacogenomic, and treatment‐related predictors of MTX response in RA. Methods A systematic search of PubMed/MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted for studies published up to May 22, 2024. Randomized controlled trials, prospective cohort studies, and registry‐based studies evaluating predictors of MTX efficacy were included. In total, 87 studies met the eligibility criteria and were included in the review. Predictors were categorized as demographic/clinical, disease‐related, serological/immunological, genetic/pharmacogenomic, treatment‐related, and emerging. Evidence was synthesized narratively, with consideration of methodological quality and consistency. Results Consistent predictors of favorable MTX response included lower baseline disease activity, better functional status, early MTX initiation, and absence of erosive disease. Male sex, older age, and moderate alcohol consumption were associated with improved outcomes, although these associations may be influenced by treatment‐related and behavioral confounders, whereas smoking and higher body mass index were linked to reduced efficacy. Several inflammatory and cellular biomarkers were associated with MTX response, although individual pharmacogenetic variants showed limited reproducibility. Treatment‐related factors, including subcutaneous administration, rapid dose escalation, glucocorticoid co‐therapy, and folate supplementation, were associated with improved efficacy and tolerability. Emerging proteomic, epigenetic, and metabolomic signatures demonstrated potential for early response prediction. Conclusions Overall, early disease control and optimized treatment strategies appear to be more reliable predictors of MTX response than isolated demographic or genetic factors. Integration of clinical predictors with emerging molecular biomarkers may support personalized treatment approaches and earlier identification of MTX non‐responders. PROSPERO Registration Number CRD42023464365.
Abstract Pregnancy in women with connective tissue disease‐interstitial lung disease (CTD‐ILD) presents a complex and high‐risk clinical scenario involving maternal health, fetal outcomes, and emerging therapeutic challenges. Despite increasing recognition of CTD‐ILD among women of reproductive age, evidence guiding pregnancy management remains limited, particularly across different levels of disease severity, with persistent gaps in understanding maternal and fetal outcomes, optimal assessment strategies, and therapeutic approaches. The paucity of high‐quality, prospective data means that clinicians must often rely on limited observational evidence, navigating a landscape of clinical uncertainty and methodological limitations. This review summarizes current evidence and highlights key knowledge gaps, with a specific focus on preconception, antenatal, and postpartum care. It emphasizes the need for coordinated, multidisciplinary approaches and calls for dedicated research frameworks, such as registries and predictive models, to improve maternal and fetal health outcomes. These findings underscore the need for individualized, multidisciplinary care within an evolving evidence base.
Background::The clinical significance of antinuclear antibodies (ANA) in Kikuchi-Fujimoto disease (KFD) remains unclear, particularly whether ANA positivity predicts progression to autoimmune diseases. This study aimed to investigate the association of ANA with clinical features and prognosis in patients with KFD.Methods::This retrospective cohort study included KFD patients confirmed by lymph node biopsy at Beijing Friendship Hospital, Capital Medical University, from January 2015 to January 2025. Patients were categorized into ANA-positive and ANA-negative groups. Clinical characteristics, laboratory parameters, treatment, and outcomes were compared.Results::A total of 140 KFD patients were included. Only 10 patients (7.1%) had concurrent rheumatic diseases at presentation. Among the remaining 130 patients without rheumatic diseases, ANA positivity was 60.0% (78/130). Other autoantibodies (including anti-Sm, anti-SSA, and anti-ribosomal P protein) were detected in 9 ANA-positive patients (11.5%), with none in the ANA-negative group ( p < 0.001). The ANA-negative group had a significantly higher proportion of female patients (58.5% vs. 37.9%, p = 0.028), while lactate levels were slightly lower in the ANA-positive group (median 1.8 vs. 1.9 mmol/L, p = 0.028). Among the 130 KFD patients without concurrent rheumatic diseases, 107 patients (82.3%) completed follow-up (median 39 months). During follow-up, six relapses (5.6%) occurred, with no significant difference between ANA-positive and ANA-negative groups (5.9% vs. 5.1%, p= 1.000). Repeat ANA testing was performed in only 15 patients (all in the ANA-positive group), of whom 11 (73.3%) seroconverted to negative. During follow-up, one ANA-positive patient was diagnosed with rheumatoid arthritis after 7 years, and another was diagnosed with ankylosing spondylitis after 9 years. No patient developed systemic lupus erythematosus or other connective tissue diseases. Conclusions::ANA positivity is common in KFD but does not necessarily indicate underlying rheumatic disease or predict progression to overt autoimmune disease. Most patients have favorable outcomes, and the short-term risk of developing connective tissue diseases is low. Longer follow-up is warranted.
Sj?gren's disease (SjD) is a chronic systemic autoimmune disorder characterised by exocrine gland dysfunction and diverse systemic manifestations. While both innate and adaptive immune dysregulation contribute to pathogenesis, growing evidence highlights a central role for regulatory T cells (Tregs) in maintaining immune tolerance and preventing autoimmunity. In SjD, Tregs display numerical reduction, impaired expansion, and functional instability, compromising their ability to suppress autoreactive lymphocytes. Moreover, the inflammatory milieu promotes Treg plasticity, with loss of Foxp3 expression and conversion into proinflammatory "ex-Tregs", further amplifying tissue damage. A key pathogenic hallmark is the disturbed Th17/Treg axis, skewed toward Th17 dominance and driven by cytokines such as interleukin (IL)-17, IL-6, and IL-23, exacerbating glandular destruction. Correlations between Treg profiles, systemic disease activity, and clinical outcomes suggest their potential utility as biomarkers for disease monitoring and therapeutic stratification. Emerging therapeutic approaches aim to restore Treg-mediated tolerance. Low-dose IL-2 therapy selectively expands functional Tregs, with promising clinical trial outcomes in SjD and related autoimmune diseases. Additional strategies include modulation of gut microbiota to enhance mucosal Treg function, adoptive transfer of ex vivo expanded or engineered Tregs, and cell-free approaches using Treg-derived exosomes. Despite these advances, challenges persist, particularly regarding Treg instability in inflammatory environments and the difficulty of generating antigen-specific therapies. Targeting Tregs represents a paradigm shift from broad immunosuppression toward precision immune restoration in SjD. By reinforcing the body's natural regulatory networks, Treg-based interventions hold promise for durable disease control and improved patient outcomes.
Background The clinical symptoms of rheumatoid arthritis (RA), such as morning stiffness and joint pain, exhibit marked diurnal variation, indicating that its pathophysiological processes may be regulated by circadian rhythms. However, the circadian characteristics of relevant inflammatory markers, bone-destructive factors, and core clock genes, as well as their interrelationships, remain to be fully elucidated.Methods A collagen-induced arthritis (CIA) model was established in rats maintained under a 12-h light/dark cycle. Serum and joint tissues were collected at six zeitgeber time (ZT) points (ZT2, 6, 10, 14, 18, 22). Serum cytokine levels were measured by enzyme-linked immunosorbent assay. The protein expression of macrophage migration inhibitory factor (MIF), Dickkopf (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) in joint tissues was analyzed by Western blotting, and the mRNA expression of core clock genes (Clock, Bmal1, Per2, Cry1) was quantified by reverse transcription-quantitative polymerase chain reaction. Data were analyzed using GraphPad Prism and IBM SPSS Statistics. Circadian rhythmicity was assessed using the R package "CircaCompare".Results In the CIA rats, serum levels of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-17, interleukin-1 beta, MIF) and bone-destructive factors (DKK-1, RANKL) were elevated during the dark phase, while OPG was decreased. In inflamed joint tissues, protein levels of MIF, DKK-1, and RANKL displayed significant circadian oscillations peaking during the dark phase, in antiphase to OPG. Furthermore, analysis of core clock genes revealed that the positive regulatory elements, Clock and Bmal1, lost their statistical rhythmicity, while the negative elements were impaired: Per2 was arrhythmic in both control and CIA groups, and Cry1 exhibited a significantly attenuated oscillation amplitude.Conclusion These findings indicate a temporal coupling among nocturnal systemic inflammation, local circadian clock disruption, and dysregulated bone metabolism in CIA rats. This coupling provides molecular insights into the diurnal symptom fluctuations characteristic of RA and suggests that chronotherapy targeting MIF or DKK-1 warrants further investigation.
Background Rapidly progressive interstitial lung disease (ILD) is a major complication in patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM) and carries a poor prognosis despite aggressive immunosuppressive therapy. Emerging evidence suggests that overactivation of the type I interferon (IFN-I) pathway may play a pivotal role in the pathogenesis of this disease. This study aimed to evaluate the activation of the IFN-I pathway in the sera of patients with MDA5-positive DM-associated ILD. Methods Serum samples were collected from clinically active patients with anti-MDA5-positive DM-associated ILD and anti-aminoacyl-tRNA synthetase (ARS)-positive polymyositis (PM)/DM-associated ILD and healthy controls (n = 22, 21, and 32, respectively). Serum IFN-I bioactivity, IFN-stimulated gene (ISG)-inducing activity, and nuclear factor kappa B (NF-kappa B) bioactivity were determined using reporter cell lines. The relationship between these results and clinical features was analyzed. Results The sera of patients with anti-MDA5-positive DM-associated ILD demonstrated significantly higher IFN-I bioactivity and ISG-inducing activity than those with anti-ARS-positive PM/DM-associated ILD and healthy controls (p < 0.01 for all comparisons). In contrast, no significant differences in NF-kappa B bioactivity were observed. Serum IFN-I bioactivity and ISG-inducing activity were moderately correlated with serum ferritin levels (r = 0.53 and 0.54, respectively). In an exploratory analysis, the serum of six patients with anti-MDA5-positive DM-associated ILD demonstrated higher ISG-inducing activity than that measured using reporter cells with a knockout of the IFNAR2 gene, and higher values of IFN-I bioactivity, ISG-inducing activity, and serum ferritin than the other samples, suggesting IFN-I overactivation, especially in these patients. Conclusions This study confirmed the hypothesis that the overactivation of the serum IFN-I pathway is strongly associated with anti-MDA5-positive DM-associated ILD. In addition, anti-MDA5-positive DM-associated ILD and anti-ARS-positive PM/DM-associated ILD may have distinct pathomechanisms.
Background In patients with rheumatoid arthritis (RA), patient-reported outcomes (PROs) may vary by disease-modifying antirheumatic drug (DMARD) class. This study aimed to assess the impact of biological/targeted synthetic DMARDs (b/tsDMARDs) on PROs in patients with sustained low RA activity or remission, compared with those treated with conventional synthetic DMARDs (csDMARDs) alone.Methods A retrospective cross-sectional study was conducted on patients who maintained low RA activity or remission for at least 6 months. PROs, including the Short Form-36, Health Assessment Questionnaire, EuroQol 5 Dimensions, Routine Assessment of Patient Index Data 3, and Functional Assessment of Chronic Illness Therapy-Fatigue scale, were assessed and compared between patients treated with csDMARDs alone and those treated with b/tsDMARDs with or without methotrexate (MTX).Results This study enrolled 102 patients with RA, and found that patients treated with antitumor necrosis factor-alpha inhibitors had better PROs compared with those treated with csDMARDs alone, particularly in role physical (coefficient: 5.37, 95% confidence interval [CI]: 0.35-10.39), role emotional (coefficient: 5.78, 95% CI: 1.04-10.52), vitality (coefficient: 5.23, 95% CI: 0.57-9.90) and mental health (coefficient: 5.58, 95% CI: 1.37-9.79). Similarly, treatment with interleukin-6 receptor inhibitors and Janus kinase inhibitors resulted in superior PROs in role physical (coefficient: 5.76 [95% CI: 0.06-11.48] and 8.99 [95% CI: 1.97-16.01], respectively) compared with csDMARDs. Furthermore, MTX use was associated with improvements in vitality (coefficient: 4.34, 95% CI: 0.14-8.54) and mental health (coefficient: 4.59, 95% CI: 0.82-8.35).Conclusion b/tsDMARDs, particularly tumor necrosis factor-alpha inhibitors, provide superior PROs in patients with sustained RA low activity or remission, with additional benefits from MTX.
Background Numerous studies have explored age-related heterogeneity in primary Sj & ouml;gren's disease (SjD); however, the links between clinical phenotypes and underlying immunophenotypes across age groups remain insufficiently defined. Because primary SjD onset is typically gradual and retrospectively uncertain, diagnostic age-corresponding to the time of confirmed disease identification and clinical management-serves as a more practical and reproducible measure for age-related analysis. Methods We retrospectively analyzed 5778 primary SjD patients from Peking University People's Hospital diagnosed between January 2018 and December 2022, stratifying them by diagnostic age (<45 years vs. >= 45 years). Multivariable logistic regression, adjusted for confounders and with false discovery rate correction, was used to identify age-dependent associations. Results In unadjusted analyses, early-diagnosed patients exhibited a distinct clinical phenotype and more active humoral immunity. Subsequent multivariable adjustment, controlling for sex, smoking, comorbidities, and inflammatory/hematologic markers, confirmed early diagnosis (<45 years) as an independent risk factor for interstitial lung disease (adjusted odds ratio [OR] = 1.98, 95% confidence interval [CI]: 1.09-3.60) and hypergammaglobulinemia (adjusted OR = 3.80, 95% CI: 2.91-4.99). Immunophenotyping further revealed a reconstituted T cell landscape characterized by CD4(+) lymphopenia (median difference: -70 cells/mu L; 95% CI: -109 to -30), CD8(+) expansion (+33 cells/mu L; 95% CI: +8 cells/mu L to +75 cells/mu L), and a skewed CD4(+) subset balance featuring elevated Treg (9.76% vs. 8.57%) and na & iuml;ve Th cells (34.90% vs. 26.30%) but reduced Teff cells (88.93% vs. 90.30%; all p < 0.01). Conclusions This study defines the core phenotype of early-diagnosed primary SjD by hypergammaglobulinemia and interstitial lung disease risk, unveiling its distinct T cell basis. These results highlight age-specific immune mechanisms and suggest the need for personalized monitoring and individualized immune regulation strategies in clinical management.
Systemic sclerosis (SSc) is a complex autoimmune disorder in which cardiovascular involvement remains a major determinant of morbidity and mortality. Cardiac injury in SSc results from the interplay of microvascular dysfunction, immune-mediated inflammation, and progressive interstitial and replacement fibrosis, leading to myocardial disease, arrhythmias, pericardial abnormalities, and coronary microvascular ischemia. Many of these manifestations evolve silently, becoming clinically apparent only after substantial structural or electrical remodeling has occurred, highlighting the critical need for systematic surveillance. Current consensus algorithms recommend a core annual cardiovascular assessment—including symptom-directed clinical evaluation, electrocardiography, transthoracic echocardiography with tissue Doppler and strain imaging, and measurement of natriuretic peptides and high-sensitivity troponin—with escalation to cardiac magnetic resonance imaging, ambulatory rhythm monitoring, or stress testing when abnormalities are detected. Management integrates standard heart failure and arrhythmia therapies with judicious use of immunomodulation in patients with active inflammatory cardiomyopathy. However, evidence for targeted immunosuppressive treatment of primary cardiac involvement in SSc remains limited, and the optimal frequency, modality, and biomarker combinations for screening continue to be refined. This review synthesizes emerging mechanisms, diagnostic strategies, and therapeutic considerations, and outlines research priorities aimed at improving early detection and outcomes in cardiovascular manifestations of SSc.
Background The farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Its role in uric acid (UA) homeostasis, however, remains unclear. This study investigated the potential involvement of FXR in hyperuricemia and explored the underlying mechanisms. Methods FXR knockout mice (n = 22) along with their littermate wild-type controls (n = 19) were used to assess serum UA concentrations and intestinal expression of ATP-binding cassette subfamily G member 2 (ABCG2). Serum UA was quantified using a phosphotungstic acid assay. A hyperuricemia model was induced in C57BL/6 mice by yeast polysaccharide supplementation and potassium oxonate injection, followed by treatment with obeticholic acid (OCA), a selective FXR agonist. FXR and ABCG2 expression was evaluated by real-time polymerase chain reaction, Western blot, and immunohistochemistry. In vitro, CT-26 cells were exposed to high UA with or without OCA, and FXR expression was silenced using siRNA. The binding of FXR to the ABCG2 promoter was tested by dual-luciferase reporter assay. Human intestinal tissues from patients with hyperuricemia (6 male/1 female) and healthy controls (5 male/1 female) were also analyzed. Results FXR knockout mice exhibited significantly higher serum UA levels than wild-type controls (550.9 +/- 106.3 vs. 336.3 +/- 52.1 mu mol/L, p < 0.001), accompanied by reduced intestinal ABCG2 expression. In hyperuricemic mice, OCA administration lowered serum UA concentrations and restored ABCG2 expression. In CT-26 cells, OCA enhanced FXR and ABCG2 expression under high UA conditions (500 mol/L), an effect blocked by FXR knockdown. Reporter assays demonstrated that FXR can activate the ABCG2 promoter. In human samples, intestinal FXR and ABCG2 expression were both significantly reduced in patients with hyperuricemia compared with controls (p < 0.05). Conclusions FXR appears to exert anti-hyperuricemic effects, at least in part, by upregulating intestinal ABCG2 expression. These findings highlight FXR as a potential therapeutic target in hyperuricemia and support further evaluation of FXR agonists in clinical settings.
Background The interplay between inflammatory disease activity and centralized pain processing represents a significant challenge in the clinical management of spondyloarthritis. In patients with spondyloarthritis, the co-occurrence of fibromyalgia may significantly influence patients' perception of their symptom burden and treatment satisfaction. This study aimed to determine the prevalence and impact of fibromyalgia and examine the association of fibromyalgia severity score (FS) and clinical parameters with Patient Acceptable Symptom State (PASS) in Thai patients with spondyloarthritis.Methods A cross-sectional study consecutively enrolled Thai patients with spondyloarthritis. Fibromyalgia was diagnosed using the 2016 revision of the 2010/2011 American College of Rheumatology criteria. Collected data included demographics, physical examination, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Pittsburgh Sleep Quality Index (PSQI), EuroQoL 5-dimensions (EQ-5D) Index, and PASS. Regression analysis identified factors associated with PASS.Results Among 218 participants, 12 (5.5%) had fibromyalgia. These patients had significantly higher median BASDAI (5.1 vs. 1.5, p = 0.001), BASFI (3.8 vs. 0.8, p = 0.004), and PSQI (8.0 vs. 5.0, p = 0.046), a lower mean EQ-5D index (0.63 vs. 0.88, p = 0.001), and fewer PASS-yes responses (8.3% vs. 72.3%, p < 0.0001). The PASS-yes group had lower median FS than the PASS-no group (2.0 vs. 6.5, p = 0.001). In multiple regression models, BASDAI < 4 (odds ratio [OR] range 4.05-4.62), FS < 3 (OR range 3.27-3.83), and PSQI <= 5 (OR range 2.01-2.40) were independently associated with PASS, whereas BASFI was not.Conclusions Fibromyalgia prevalence is elevated in patients with spondyloarthritis, and significantly impairs health-related quality of life and symptom perception. Low disease activity, good sleep quality, and FS < 3 are independently associated with achieving an acceptable symptom state. These findings highlight the importance of assessing fibromyalgia to better understand patient-reported outcomes and guide clinical decision-making.
